The present invention relates to a method for the treatment of acute renal failure (ARF) and, more particularly, to a method for improving the recovery from acute renal failure by treatment with zaprinast. (Note: Literature references on the following background information and on the conventional test methods and laboratory procedures well known to the ordinary person skilled in the art and other such state-of-the-art techniques as used herein are indicated in parentheses and appended at the end of the specification.)
Acute renal failure (ARF) is a major problem in contemporary medicine.
Five percent (5%) of all hospitalized patients are affected by some degree of acute renal dysfunction (1). PA0 Fifty percent (50%) of all patients diagnosed with ARF will die, thus demonstrating the morbidity and mortality associated with this disease (2). PA0 In various clinical situations, such as intensive care medicine, post cardiovascular surgery, and after cadaveric renal transplantation, the incidence of acute renal failure has been reported to be between 50% and 75% (1,3). PA0 The decrease in GFR is most likely a result of both tubular obstruction and afferent arteriolar vasoconstriction (4). PA0 In most circumstances, the kidney will recover from such an insult; however, in many cases, recovery does not occur prior to the need for temporary dialysis or the onset of other complications associated with ARF. Numerous non-pharmacologic and pharmacologic strategies have been attempted to enhance recovery from an acute ischemic injury. These include inducing and osmotic diuresis with mannitol, the use of loop diuretics to maintain high tubular urine flow rates, and the low dose infusion of dopamine to increase GFR (1,33,34). PA0 More recently, exogenous administration of peptides such as Atrial Natriuretic Factor (ANF) (9,10,15,16) and insulin-like growth factor I (23,31) have been infused in pharmacologic doses and have accelerated renal recovery and regeneration. PA0 Proposed pathophysiologic mechanisms for ARF include tubular obstruction and/or a reduction in glomerular filtration rate (GFR) (4). PA0 ANF increases GFR and stimulates tubular fluid and sodium flow (5-8); therefore, it should be ideal in the treatment of ischemic ARF. PA0 Recent experimental studies have shown that both ischemic and nephrotoxic ARF may be effectively attenuated by ANF or ANF synthetic analogs administered before or after the onset of renal injury (9-18). PA0 ANF, as well as its synthetic analogs, stimulate the activation of the particulate guanylate cyclase, increase intracellular cGMP production, and cGMP appears to mediate many of the biological functions of ANF (19-21). PA0 Interestingly, inhibition of nitric oxide (NO), an activator of the soluble guanylate cyclase, by L--N.sup.G -nitroarginine worsens ischemic renal dysfunction (22,23). PA0 These results indicate that cGMP may be the common denominator responsible for the improvement seen in ARF in response to ANF or NO. PA0 1. Hypoperfusion, resulting from sepsis, congestive heart failure, etc; PA0 2. Surgery, e.g., from cross-clamping; PA0 3. Medication, e.g., by inhibitors of angiotensin-converting enzyme (ACE), antibiotics, and drugs causing interstitial nephritis; and PA0 4. Contrast agents used in angiograms and various other diagnostic scans.
Under most conditions, it is not possible to predict who will develop ARF. Thus, identification of a pharmacologic intervention that would be effective in the treatment of established renal failure would be a significant therapeutic breakthrough. The kidney is a remarkably regenerative organ. A significant decrease in renal artery blood flow will result in severe tubular epithelial cell destruction, intrarenal hemorrhage, and a prolonged decrease in glomerular filtration rate (GFR).
Another potential strategy to increase the intracellular level of cGMP is by inhibiting its degradation to the corresponding nucleoside 5'-monophosphate. This hydrolysis is catalyzed by cyclic nucleotide phosphodiesterases (PDEs) which exist in multiple distinct forms in many tissues (24-27). These PDE isozymes represent the sole mechanism for degrading cGMP and cyclic adenosine monophosphate (cAMP) and therefore play an important role in determining their intracellular concentration.